Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients

J Pharmacokinet Pharmacodyn. 2011 Feb;38(1):105-19. doi: 10.1007/s10928-010-9180-2. Epub 2010 Nov 20.


The precise assessment of the dose-response to bronchodilators in the treatment of chronic obstructive pulmonary disease is hindered by the low signal to noise ratio of the typical clinical endpoint FEV(1). Kinetic-pharmacodynamic (K-PD) models which use time course of response over a range of doses are in principle suited for the assessment of the dose response relationship of pulmonary administered drugs. A K-PD model was successfully developed using the longitudinal FEV1 data collected in the clinical study for a novel bronchodilator X. A superposition of two cosine functions was selected to describe the circadian variability in FEV(1) at baseline. The onset (ka) and offset (kde) of drug action were described with first-order rate constants of 0.214/h and 0.141/h, respectively. Drug potency, EKD(50,) was estimated as 6.56 μg/h, and the maximum response, Emax as 0.631 L. Between-subject variability for kde, EKD(50) and Emax were 65, 84.7 or 34.4% (expressed as coefficient variation). The model-based simulation predicted that for the same total daily dose of once-daily and twice-daily regimens, the trough FEV(1) response to a twice-daily regimen was higher, and the maximum FEV(1) response to once-daily regimen was higher, while the predicted average FEV(1) response was about the same.

MeSH terms

  • Administration, Inhalation
  • Bronchodilator Agents / pharmacokinetics*
  • Bronchodilator Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Forced Expiratory Volume / drug effects*
  • Humans
  • Models, Biological
  • Models, Statistical*
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Respiratory Function Tests
  • Scopolamine Derivatives / pharmacokinetics*
  • Scopolamine Derivatives / pharmacology*
  • Spirometry
  • Time Factors


  • Bronchodilator Agents
  • Scopolamine Derivatives